Treatment of pruritus with topically appliedopiate receptor antagonist

Paul L. Bigliardi, MD,a,b Holger Stammer, MSc,d Gerhard Jost, MD,c Theo Rufli, MD,b

Stanislaw Buchner, MD,b and Mei Bigliardi-Qi, PhDa,b

Lausanne, Basel, and Egerkingen, Switzerland; and Munich, Germany

Background: Pruritus is the most common and distressing skin symptom, and treatment of itch is aproblem for thousands of people. The currently available therapies are not very effective. Therefore there isan urgent need to find new effective topical drugs against itching.

Objective: We conducted two separate studies to evaluate the efficacy of topically applied naltrexone,an opioid receptor antagonist, in the treatment of severe pruritus. The objective of the first open studywas to correlate the clinical efficacy of topically applied naltrexone in different pruritic skin disorders to achange of epidermal �-opiate receptor (MOR) expression. The second study was a double-blind, placebo-controlled, crossover study on pruritus in atopic dermatitis.

Methods: Initially we performed an open pilot study on 18 patients with different chronic pruriticdisorders using a topical formulation of 1% naltrexone for 2 weeks. A punch biopsy was performed in 11patients before and after the application of the naltrexone cream and the staining of epidermal MOR wasmeasured. Subsequently, a randomized, placebo-controlled, crossover trial was performed with the sameformulation. We included in this trial 40 patients with localized and generalized atopic dermatitis withsevere pruritus.

Results: In the open study more than 70% of the patients using the 1% naltrexone cream experienceda significant reduction of pruritus. More interestingly, the topical treatment with naltrexone caused anincrease of epidermal MOR staining. The regulation of the epidermal opioid receptor correlated with theclinical assessment. The placebo-controlled, crossover trial demonstrated clearly that the cream containingnaltrexone had an overall 29.4% better effect compared with placebo. The formulation containingnaltrexone required a median of 46 minutes to reduce the itch symptoms to 50%; the placebo, 74 minutes.

Limitations: We could only take biopsy specimens in 11 patients, which means that a satisfactory statisticalanalysis of the changes of epidermal MOR staining was not possible. In addition, there was an insufficientnumber of patients with nephrogenic pruritus and pruritic psoriasis to draw definitive conclusions.

Conclusions: The placebo-controlled study showed a significant advantage of topically applied naltrexoneover the placebo formulation. This finding is supported by the biopsy results from the open studies, showinga regulation of MOR expression in epidermis after treatment with topical naltrexone, especially in atopicdermatitis. These results clearly showpotential for topically appliedopioid receptor antagonist in the treatmentof pruritus. The placebo formulation also had some antipruritic effects. This underlines the importance ofrehydration therapy for dry skin in the treatment of pruritus. ( J Am Acad Dermatol 2007;56:979-88.)

Pruritus or itch is defined as an unpleasantsubjective sensation associated with the de-sire to scratch. Pruritus induces a mechanical

From the Departments of Dermatology, CHUV Hopital Beaumont,

Lausanne,a and the University of Baselb; Spirig AG, Egerkin-

genc; and Pharmalog GmbH Institute for Clinical Research,

Munich.d

Funding sources: Spirig AG, Egerkingen and the Department of

Dermatology, University of Basel.

Conflicts of interest: None declared.

Accepted for publication December 14, 2006.

defense reaction, including pressing, rubbing, orscratching. The scratching leads to new irritationof the skin and this in turn induces pruritus, which

Reprint requests: Paul L. Bigliardi, MD, Department of Dermatology,

Neurodermatology, CHUV Hopital de Beaumont, BT-440, CH-

1011 Lausanne, Switzerland; phone 1141 21 314 01 11, fax

1141 21 314 03 82. E-mail: paul.bigliardi@chuv.ch.

Published online March 6, 2007.

0190-9622/$32.00

ª 2007 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2007.01.007

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creates a vicious circle.1 Pruritus is the most commonand distressing skin symptom. The treatment of itchis a problem for thousands of people and is impor-tant not only for dermatology but also for allother medical specialties. The currently availabletopically applied drugs for pruritus, such as theantihistamines or polidocanol, are restricted by theirlimited efficacy when used by this route of adminis-tration and by their ability to sensitize. In addition,most patients with chronic pruritus do not respondto systemic treatment with antihistamines or steroids.Therefore there is an urgent need to find new effectivedrugs against itching.

For many years it has been suggested that the itchsensation is related to pain, and, indeed, the opioidpeptides can influence the pain and itch sensation ina reversed way. Pruritus is a well-known and hard-to-control side effect of treatment with opioids forpain relief.2 On the other hand, opioid-receptorantagonists, such as naltrexone and naloxone, havebeen used to treat different forms of chronic pru-ritus.3-5 There have been several double-blind,placebo-controlled studies proving the effect ofsystemically applied naltrexone and naloxone inhepatogenic pruritus.6-8 In addition, plasma frompatients who have pruritus associated with chroniccholestasis inducedopioid receptoremediated scratch-ing in monkeys,9 and naltrexone treatment of thispruritus in humans precipitated an opioid withdrawal-like reaction.10 These observations suggest a crucialrole of the opioid receptor system and its ligands,such as b-endorphin, in chronic cholestatic pruritus.Systemically applied naltrexone reduced itching notonly in patients with hepatogenic pruritus, but also inthosewithdifferentpruritic skindiseases, suchas atopicdermatitis, xerosis cutis, cutaneous lymphoma, andprurigo nodularis.4 However, systemic naltrexoneseemed to have no significant effect against uremicpruritus in a double-blind, placebo-controlled study.11

There is still an ongoing discussion as to whetherthis elicitation of itch is due to opioid receptors in thecentral nervous system (CNS) or in the peripheralnervous system. One of the most important indica-tions that the opioid-induced pruritus is at leastpartially elicited in the periphery comes from thedouble-blind controlled studies with the opioid

Abbreviations used:

CNS: central nervous systemFAS: full analysis setMOR: �-opioid receptorPP: per protocolSPID: sum of the pruritus intensity differenceVAS: visual analogue scale

receptor antagonist methylnaltrexone. Methylnal-trexone, a novel quaternary derivative of naltrexonethat does not cross the blood-brain barrier, acts as aselective peripheral opioid receptor antagonist anddecreases pruritus and constipation, but still has anadequate maintenance of pain control.2,12 This indi-cates that pruritus is elicited in the peripheral ner-vous system and modified in the CNS. Thereforewe wanted to study the effect of a topically appliedopioid-receptor antagonist against different forms ofpruritus.

METHODSStudy objectives and design

Open pilot study. The main objective of thisstudy was to see whether the topical application ofthe opioid-receptor antagonist naltrexone has anantipruritic effect and whether there is an objectiveeffect, as studied by immunohistology. Therefore intwo study centers we treated 18 patients with differ-ent pruritic disorders with a cream containing 1%naltrexone to see which kind of pruritus respondsbetter to this treatment. The patients had to apply thestudy cream at the itching locations at least twice aday. The general intensity of the pruritus was mea-sured by using a visual analogue scale (VAS) from1 to 100 mm and the patients had to record theintensity of pruritus in their diaries in the morning,at noon, and in the evening. In addition, after 8 and15 days the patient had to assess, together with thephysician, the overall changes of pruritus. The clin-ical efficacy was judged according to the changesof the scratching intensity in the VAS as noted inthe diary compared with day 0 (start of study).Additionally, in 11 patients we carried out a punchbiopsy at the site of intense itching before and afterthe local treatment with the opioid receptor antag-onist. The epidermal expression of �-opiate receptor(MOR) and the changes of epidermal nerve endingswere observed and semiquantified by immunohis-tochemistry using confocal microscopy. This pilotstudy showed that the topically applied opioidreceptor antagonist worked best on patients withchronic pruritus associated with atopic dermatitisand lichen simplex chronicus.

Placebo-controlled, crossover study. We plan-ned a second multicenter, randomized, double-blind,placebo-controlled, crossover, phase II study onpatients with atopic dermatitis. The goal of this studywas to confirm in a double-blind study design thattopically applied naltrexone indeed has an antipru-ritic effect in atopic dermatitis. The study took 4 to 6weeks and included 40 patients with severe attacks ofpruritus. The patients were required to visit the studycenter 4 times:

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d Visit 1: 14 days, wash-in phased Visit 2: Day 0, randomization of the patient and

start of therapy with one creamd Visit 3: control of patient’s diary and change of

cream; day 7 or 14, depending on whether thepatient had had 3 severe bouts of scratching in1 or 2 weeks

d Visit 4: collection of creams, control of diary, finalquestionnaire and end of study; day 14, 21, or 28

The diary was not only used to record the itchsensation during the bouts of itching, but also torecord the location of the pruritic attacks, the use ofrescue medication, and side effects. The patients hadto go through a wash-in phase of 2 weeks, wherethey could apply the normal basic treatment of theatopic dermatitis with their own rehydrating creamand, if necessary, the previous therapies such assystemic antihistamines. During these 2 weeks thepatients had to record 3 bouts of itching ([50 mmVAS). The intensity of the pruritus was recorded ina patient diary at the following times: 0 hours (startof study), 20 minutes, 40 minutes, 1 hour, 2 hours,3 hours, and 4 hours. Overall, only a few pruritusattacks were not documented completely over 4hours. However, in those cases, missing values wereimputed by the last available documentation (alsocalled ‘‘last value carried forward’’ principle). This isa conservative method commonly used in placebo-controlled trials.

The patients were randomized and they enteredthe study with the placebo or the naltrexone-creamin a double-blind study design. The basic treatmentof the dry skin was continued unchanged during theentire duration of the study. The patient had again torecord 3 severe bouts of itching during 1 or 2 weeksin the patient diary. If the patient experienced severepruritus, he or she applied the study cream topicallyand recorded the itch sensation on a VAS at the timepoints mentioned above. The patient had to experi-ence, treat, and record at least 3 severe bouts ofitching (VAS[50 mm) in 2 weeks. After 1 to 2 weeksthe study cream was changed in a crossover studydesign and the patient had again to record and treat3 severe bouts of itching in 1-2 weeks. The patientswere allowed to use the study cream freely during thestudy, also against other attacks of pruritus.

Selection of study participantsFor the open study, patients were chosen who had

a severe chronic pruritus of different origin. Allof these patients previously had several differentunsuccessful treatments. The diagnoses of the differ-ent patients can be seen in Table I. Patients youngerthan 18 years and pregnant woman were excluded.

This study was performed in Switzerland (Basel andSchaffhausen).

The second, double-blind study included patientsolder than 18 years with atopic dermatitis. They wererecruited in 3 different study centers in Germany.The bouts of pruritus had to be more than 50 mm ina VAS from 0 to 100 mm, which represents a pruritusof strong intensity. Exclusion criteria were infectiousskin diseases, known allergies against the ingredi-ents of the drugs, acute eczema, malignant diseases,drug abuse, severe neurological or psychologicaldiseases, and pregnancy. Two weeks before andduring the study, the patients were not allowed touse the following drugs: systemic opioids and theirantagonists, systemic steroids and antibiotics, topicaltacrolimus or pimecrolimus. As rescue medication,topical steroids were allowed to be used, but thepatient had to record this, and the use of topicalsteroids was not allowed during the time of mea-surements of itching intensity.

Immunostaining and semiquantificationof epidermal PGP 9.5 and MOR staining(open study)

With informed consent, 3-mm punch biopsyspecimens were taken from pruritic skin just beforelocal treatment with naltrexone. Two weeks afterregular application of naltrexone cream, another3-mm punch biopsy specimen was taken from thesame area (;1 cm away from the first biopsy). Thebiopsy specimens were fixed for at least 12 hours in4% formaldehyde and embedded in paraffin. Theparaffin-embedded skin biopsy sections were cut,dried overnight at 378C, and deparaffinized. Theprimary antibody used for immunofluorescence wasa polyclonal rabbit antie�-opioid receptor antibody(Diasorin). A cyanine dye (Cy2)econjugated goatanti-rabbit IgG for MOR was used as a secondaryantibody. Confocal microscopy was performed witha Zeiss Confocal Laser Scanning Microscope LSM510, inverted Axiovert 100 M (Carl Zeiss AG, Jena,Germany). It operates in the sequential acquisitionmode to exclude cross talk between channels. The488 excitation line was used and the optics used wasa Zeiss Plan-Neofluar 403 oil immersion objectivewith a numerical aperture of 1.3. Optical sections, 0.9�m thickness, were scanned through the z-plane ofthe sample. The amount of fluorescent staining inepidermis was semiquantified by using the Imarisstatistic software package.

Efficacy and safety evaluationsSwiss ethical committees approved the open pi-

lot study in 2001 (E 407/01). The double-blind studywas approved by German (number 03182 of the

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Table I. Correlation of clinical efficacy of naltrexone cream to epidermal MOR expression(immunofluorescence) in the open pilot study

Patient No. Age (y) Skin disease Clinical efficacy Change of MOR expression Location of biopsy

01 74 AD � � Finger02 79 Prurigo simplex 11 1 Back03 22 AD 1 1 Upper arm05 46 LSC 11 1 Lower leg07 38 Nephrogenic pruritus � = Elbow08 61 Prurigo simplex 1 1 Upper arm09 46 AD 11 = Upper arm11 20 AD 1 11 Upper arm12 40 AD 11 1 Upper arm13 46 Psoriasis inverse 11 11 Shoulder14 63 Nephrogenic pruritus 1 � Upper arm

AD, Atopic dermatitis; LSC, lichen simplex chronicus; MOR, �-opioid receptor.

‘‘Bayerische Landesarztekammer’’) and Swiss (E 248/03) ethical committees in 2003. Systemic naltrexonehas been used for many years in daily concentrationsbetween 50 and 100 mg against opioid overdoses,alcohol dependence, and, as already mentioned,against different kinds of pruritus. The safety profileand the side effects of systemic naltrexone are wellknown, and this knowledge can be applied to thetopical applications of naltrexone. In-vitro assess-ment (human skin mounted in Franz diffusion cells,exposure to the test preparation for 6 hours) re-sulted in an epidermal naltrexone concentration of3.3 �g/cm2, corresponding to 6.5% of the applieddose.

The compositions of the study creams were asfollows:

d Placebo cream: based on Excipial Cream, SpirigAG, Egerkingen, Switzerland (purified water,paraffin, myristyl alcohol, cetyl alcohol, glycerylmonostearate, polysorbate 20, citric acid, methyl-and propyl parabene, hexamidine diisetionate)

d Naltrexone cream: 1% naltrexone in aforemen-tioned Excipial Cream

Statistical analysisFor the histologic data from the open pilot study,

logarithmic and square transformations were usedto stabilize the variance of the semiquantitativemeasurements of epidermal MOR staining. Thedata are divided into two categories: before and aftertreatment. The clinical efficacy is coded by twocategories: efficient = 1, no effects = 0. The samplesize is relatively small; therefore we chose a mixedlinear model (Laird and Ware, 1982; Pinheiro andBates, 2000) to explore the difference between theefficacy and the time (before/after treatment). Thistype of model considers the individual variability of

each subject, and each subject was considered as arandom draw in the large population.

The double-blind, placebo-controlled crossoverstudy was subjected to rigorous statistical analysis.The efficacy data were based either on the FullAnalysis Set (FAS-collective) or the Per Protocol pop-ulation (PP).Thepatientsusinga ‘‘rescuemedication,’’such as topical steroids, during the first 20 minuteswere excluded from the PP analysis. Therefore the PPpopulation includes only the patients who finishedthe study without relevant deviation from the proto-col. The analysis of the safety data included allrandomized patients who were treated at least oncewith the study medication (safety evaluation set).Results were considered to be statistically significantwhen the test revealed a P value of .05 or less.

Forty-five patients were enrolled into the placebo-controlled study, and all patients were treated (safetyevaluation set), but 5 patients had a relevant viola-tion of the study protocol and were therefore ex-cluded. Three of the patients cancelled the informedconsent during the study and 2 patients had fewerthan 3 pruritus attacks of more than 50 mm VAS inboth or one of the study periods. Finally, the FAScollective contained 40 patients and the PP popula-tion, 39 patients. One patient used a topical steroid as‘‘rescue medication’’ before the end of the 4-hourobservation period in several itching attacks. ThePP population did not include this patient whohad deviated from the study protocol. The random-ized groups ‘‘placebo-naltrexone’’ and ‘‘naltrexone-placebo’’ showed no significant differences in theFAS population with regard to age (P = .75), gender(P = .30), weight (P = .39), and height (P = .18).

The duration of pruritus in the study collectivevaried between 3 years and 1 week (mean, 14.5 6

29.9 weeks). Twenty-five of the 40 patients (62.5%)had pretreatment of the pruritus; the rest had not

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treated the itching symptoms before entering thestudy. Most of the pretreatment consisted of topicalsteroids; only 4 patients had systemic antihistamines.The concomitant medications during the studiesincluded mostly drugs for cardiovascular diseases(n = 7), pain relievers (n = 3), the antidepressantmaprotiline (n = 1), omeprazole (n = 1), simvastatin(n = 1), bezafibrate (n = 1), and thyroxine againsthyperthyreosis (n = 1). None of the patients tookantihistamines during the study period and none ofthem had ultraviolet irradiation therapy.

The most important statistical parameter was the‘‘sum of the pruritus intensity difference’’ (SPID) thatis calculated from the VAS as follows:

SPID ¼ SUM i¼1 to n ðVAS½i� � VAS½Baseline�Þ

Where i = 1 is the first and n the last time point ofpuritus measurement.

The mean SPID value from 3 recordings of boutsof itching was calculated for each time point afterapplication of study cream (time 0). The change ofintensity of pruritus sensation during the first 4 hoursafter application of the cream was the most impor-tant parameter measured (SPID [Dmm VAS]).

In addition to the SPID, other criterion wereobserved. One of them was the dynamic study ofthe intensity of the pruritic attacks during time inabsolute values (mm VAS) and not relative to base-line. Another measurement concerned the rate ofresponders (defined as improvement of 10% com-pared with placebo) and the time needed until a50% reduction of the itch sensation occurred.

RESULTSPilot study

The analysis of the patients’ diaries revealed thefollowing: Most of the patients recorded relief ofpruritus in the first 15 minutes after application of thenaltrexone cream. Most of the time the effect lastedfor at least 4 hours. Most of the patients with atopicdermatitis, lichen simplex chronicus, and prurigosimplex, as well as the patient with pruritic psoriasisinversa experienced good to excellent clinical re-duction of pruritus. Biopsy sections were takenbefore and 2 weeks after initiation of the treatmentin 11 of the 18 patients. The biopsy specimen wastaken at the start of the open study (time 0) from thelocation with the most severe sensation of pruritus.Another punch biopsy specimen was taken from thesame location 2 weeks after regular application ofnaltrexone cream. The epidermal expression of MORwas semiquantified by immunohistochemistry andconfocal microscopy. Table I summarizes the clinicaland histologic results of the open pilot study.

Figs 1, A and 2, A show the typical reduction ofepidermal MOR staining in chronic pruritic skindisorders, such as atopic dermatitis or lichen simplexchronicus, compared with findings from skin biopsyspecimens of normal individuals without pruritus(see also Bigliardi et al13 and Bigliardi-Qi et al14).However, 2 weeks after regular treatment with topi-cally applied opioid-receptor antagonist, the epider-mal MOR staining is greatly increased. This increasedstaining for MOR was most pronounced in thegranular layer in atopic dermatitis (Fig 1, B). How-ever, in lichen simplex chronicus (Fig 2, B) andprurigo simplex (data not shown), the up-regulationof MOR was observed in all layers of epidermis. Onepatient with atopic dermatitis experienced no clinicalimprovement of the pruritus with naltrexone. Thispatient had an acute dyshidrotic flare of atopic handeczema; all other patients with atopic dermatitisexperiencing good clinical efficacy had chronic

Fig 1. Typical down-regulation of epidermal MOR ex-pression in a patient (patient 03) with atopic dermatitis(A). Up-regulation of epidermal MOR expression in thispatient at the same place 2 weeks after regular topicalapplication of 1% naltrexone in the open study (B).

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atopic dermatitis. In this particular patient there wasno change of the epidermal MOR staining, and thiscorrelated with the missing clinical effect. In addi-tion, patients with nephrogenic pruritus did notreport clinical improvement of the pruritus and theepidermal MOR expression did not change either.Fig 3 shows the boxplot representation of theepidermal MOR expression after logarithmic trans-formation and statistical analysis of the data. Thepatients without clinical efficacy [eff = 0] (1 atopicdermatitis, 1 nephrogenic pruritus) did not have achange of epidermal MOR expression. However, inthe 9 patients with clinical improvement of thepruritus [eff = 1] there was an increase of epidermalMOR staining. However, the number of patients wasinsufficient to develop a statistical model to calculatethe P values. The topical treatment was especiallysuccessful in patients with chronic atopic dermatitis.Therefore we decided to design a double-blind,

Fig 2. Typical down-regulation of epidermal MOR ex-pression in a patient (patient 05) with lichen simplexchronicus (A). Up-regulation of epidermal MOR expres-sion in this patient at the same place 2 weeks after regulartopical application of 1% naltrexone in the open study (B).

placebo-controlled study with patients who hadatopic dermatitis.

Double-blind, placebo-controlled,crossover study

The SPID analysis shows an advantage of thenaltrexone cream over the placebo cream of �51.6mm VAS in the FAS population (�190 mm vs �243.3mm). The placebo cream itself has an antipruriticeffect if compared with the wash-in phase. However,the overall effects and the time until the antipruriticeffect was obtained were different. The time wascalculated until the patients felt a 50% reduction ofthe pruritus compared with the value at time 0. Thusthe 50% reduction in pruritus intensity occurred after

Fig 3. Boxplot representations of MOR (with logarithmictransformation) in relation to efficacy (eff = 0 [no clinicalimprovement of pruritus]/eff = 1 [with clinical improve-ment of pruritus]) and time (before/after treatment withtopical naltrexone) in the open study.

Fig 4. Time course of score measuring 50% reduction ofpruritus in VAS (FAS population, n = 40). The Wilcoxontest revealed statistically significant difference betweenplacebo- and naltrexone-cream (P = .0073); randomized,placebo-controlled, crossover trial.

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Table II. Statistical analysis of the sum of the pruritus intensity difference values* (mm VAS) of the full analysisset and per-protocol population in total and with or without pretreatment of the pruritus: A randomized,placebo-controlled, crossover trial

Parameter

No. of

patients

Different treatments

(D mm VAS)

Global H test

(Hotelling)*

t Test to

residual effect*

t Test to

treatment

effect*

SPID: TotalFAS 40 P = �190.7; N = �242.3; D = 52.6 (26.7%) .1125 .7294 .0347PP 39 P = �192.8; N = �249.6; D = 56.8 (29.4%) .0708 .8035 .0206

SPID: Withoutpretreatment

FAS 15 P = �200.0; N = �216.4; D = 16.4 (8.2%) .7929 .8008 .5292PP 15 P = �205.1; N = �219.3; D = 14.2 (6.9%) .8428 .8751 .5713

SPID: Withpretreatment

FAS 25 P = �185.2; N = �257.9; D = 72.7 (39.3%) .0859 .3741 .0328PP 24 P = �185.1; N = �268.7; D = 83.4 (45.1%) .0594 .5186 .0165

FAS, Full analysis set; N, naltrexone; P, placebo; PP, per protocol [population]; SPID, sum of the pruritus intensity difference; VAS, visual

analogue scale.

*Data given are P values.

74 minutes with the placebo cream and after 46minutes with the naltrexone cream (Fig 4). Thismeans that the patients felt a 50% reduction ofpruritus 28 minutes earlier compared with thoseusing placebo. Fifty percent reduction of VAS after1 hour occurred with the naltrexone formulation in60.2% (placebo = 47.9%) and after 4 hours in 80.6%(placebo = 69.7%). The numbers of documentedpruritus attacks were as follows: n = 112 for thenaltrexone-formulation and n = 115 for the placebo.The Wilcoxon test revealed a significantly faster reliefof pruritus with naltrexone cream compared with theplacebo (P = .0073). The arrows in Fig 4 depict themedian. Statistical analysis of the effects of naltrex-one cream versus placebo using the Student t testshow a significant amelioration of pruritus in thenaltrexone group at 20 minutes (P = .0370), 40minutes (P = .0382), 1 hour (P = .0281), and 2 hours(P = .0404), but no longer at 3 hours (P = .0775) or4 hours (P = .1664) after application of the studycreams. Thus naltrexone in the present formulationhas its major effect on pruritus in the first 2 hoursafter application. The difference between placeboand naltrexone is particularly pronounced 20 min-utes after application of the cream. The Dmm VASvalue at 20 minutes was �15.6 mm for placebo and�23.5 mm for naltrexone. Therefore naltrexone hasa 50.6% advantage over placebo at 20 minutes,indicating that the effect of the topically appliedopioid-receptor antagonist naltrexone is very fast. Inaddition, the statistical analysis has shown that thereis no residual effect. This means that there is nosignificant difference if the patient used placebo ornaltrexone cream first in the crossover study.

Surprisingly, there is an important difference inefficacy of topically applied naltrexone if the loca-tion of itch and application is investigated. Applica-tion of the naltrexone cream on the trunk shows nooverall difference of antipruritic effects comparedwith placebo (changes in VAS after 2 hours: naltrex-one = �34.1; placebo = �35.1). However, using thelocation ‘‘arms and legs,’’ an important advantage ofnaltrexone over the placebo cream could be observed(changes in VAS after 2 hours: naltrexone = �55.9;placebo = �39.4).

Overall, naltrexone cream had a considerableadvantage over the placebo cream during the 4-hour observation period after the pruritic attack.Topically applied naltrexone has an advantage of26.7% in the FAS dataset and 29.4% in the PPpopulation over the placebo cream with respect tothe SPID measurement. The PP population includesall the patients who finished the study withoutrelevant deviation from the protocol. The globalH-test (Hotelling) and the t test for the effect oftreatment show a somewhat significant advantageof the topically applied naltrexone over placebo.The treatment effect was significantly superior in thenaltrexone group (Table II).

Fifteen patients had no pretreatment of the pru-ritus before entering the study. Observations fromclinical and basic research suggest, however, thatthere is a difference between chronic and acutepruritus in pathogenesis and treatment.14 Thereforewe analyzed the subpopulation of patients withoutpretreatment and compared them with the patientswith pretreatment of pruritus. We can hypothesizethat the patients without pretreatment of the severe

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pruritus had an acute form of pruritus, whereaspatients with pretreatment had a chronic form. Thisanalysis revealed surprising results (Table II). Thepatients without pretreatment had no advantagefrom the topical treatment with naltrexone (8.2%FAS; 6.9 PP). However, in the patients with pretreat-ment of the pruritus there was a significant amelio-ration of the pruritus by topical application ofnaltrexone (39.3% FAS, 45.1% PPl treatment effect,P = .0165). The median duration of pruritus beforeentering the study was 4 weeks in the populationwithout pretreatment and 7.5 weeks in the popula-tion with pretreatment. This means that, in general,the patients with pretreatment had had the pruritusmuch longer than patients without pretreatment.

DISCUSSIONOn the basis of our previous observations, that the

MOR system is regulated in chronic atopic dermati-tis,14 and on the basis of several clinical studies usingthe opioid-receptor antagonist naltrexone systemi-cally to treat chronic itch, we decided to put naltrex-one into a cream formulation at a concentration of1% and to study the effect of topically appliedopioid-receptor antagonist on chronic pruritus.

The first open prospective pilot study includedpatients with a pruritic skin disease not respondingto traditional treatment with antihistamines or topicalsteroids. More than 70% of these patients with severepruritus experienced a significant reduction of itch-ing after 15 to 30 minutes and the effect held for 2 to6 hours. The patients with chronic itch sensation dueto atopic dermatitis, lichen simplex chronicus, andprurigo simplex responded better to this treatmentthan those with nephrogenic pruritus. The subjectiveclinical results could be backed up by an objectivelymeasurable up-regulation of epidermal MOR stain-ing in the stratum granulosum and stratum spino-sum. The MOR expression increased in patients withgood clinical response after topical treatment withthe opioid-receptor antagonist naltrexone, but not inpatients with no efficacy of the naltrexone. In the twopatients with nephrogenic pruritus, one reported noeffect with topical naltrexone and the other only aslight effect. The expression of epidermal MOR didnot increase in either patient. The number of patientswith nephrogenic pruritus is limited in this study.However, Peer et al11 reported no significant ame-lioration of severe resistant pruritus in 15 patientsreceiving hemodialysis in a randomized, double-blind, placebo-controlled, crossover trial using sys-temic naltrexone. These data could agree with ourobservations, but further studies are needed toconfirm the limited efficacy of naltrexone in neph-rogenic pruritus.

After these very encouraging results we designeda double-blind, placebo-controlled, crossover studyusing patients with pruritus in atopic dermatitis. Thisstudy demonstrated clearly that the formulationcontaining naloxone compared with placebo hadan overall 29.4% better effect, and that relief of itchsymptoms was significantly faster. The naltrexonecream reduced itch symptoms to 50% in a medianof 46 minutes compared with 74 minutes for theplacebo formulation.

The statistical analysis showed that topical appli-cation of naltrexone had much less effect if the site ofpruritus was the trunk rather than the extremities.What could explain these differences? First, thedensity of intraepidermal nerve fibers in a healthysubject shows a rostral-to-caudal decrease, with alinear relationship to the distance from the spine.15-17

This effect is not age related. The changes of intra-epidermal nerve fibers could explain why skin onthe trunk responds less to naltrexone treatment thanskin of the extremities. However, the differencecould be also explained by differences of applica-tion. It is much easier to apply a cream on theextremities than on the back.

The placebo-controlled study shows that thereis a significant difference between the efficacy ofnaltrexone cream and placebo cream, especially ifonly the patients whose severe pruritus was pre-treated are considered. These patients had pruritusfor an average of 7.5 weeks before initiation of thestudy; this pruritus, which had a longer pretreatmentduration, could be considered chronic. The resultsshowed significant effects of the topical applicationof naltrexone in patients with long-lasting pruritus(45% alleviation of pruritus by VAS measurementcompared with placebo, n = 24), but not in patientswith pruritus that had lasted for a shorter time andwithout pretreatment (7%, n = 15). This findingagrees with previous data, which have shown thatthe down-regulation of MOR expression is especiallypronounced in chronic pruritic skin disorders witha long-lasting history of pruritus.14

We have previously demonstrated that humanepidermal keratinocytes, fibroblasts, and melano-cytes express MOR at both the mRNA and proteinlevels.13 The studies of Kauser et al18,19 and Standeret al,20 which showed an expression of MOR inepidermal and follicular keratinocytes, in sebaceousglands and melanocytes, have confirmed this find-ing. Several research groups could demonstrate thatMOR is not only expressed in keratinocytes but alsoon unmyelinated peripheral nerve fibers in thedermis and epidermis.20,21 Three-dimensional con-focal microscopy revealed that in patients withchronic atopic dermatitis the nerve endings are

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Fig 5. Interaction between opioid receptor on keratinocytes and nerve endings and relation-ship to itch signal. In normal skin, keratinocytes express high amounts of MOR; thereforeendogenous ligands are bound primarily to opioid receptors on keratinocytes, competing withbinding of opioid ligands on opioid receptors located on nerve endings. This results in a weakitch signal to the central nervous system (CNS). In chronic pruritic skin disorders, most opioidreceptors on keratinocytes are internalized; therefore there are many opioid ligands availableto bind to opioid receptors on sensory nerve endings. This leads, together with the changedmorphology of the epidermal nerve endings, to a strong itch signal to the CNS.

much thinner and run straight through the epider-mis.14 In normal skin the nerve endings are ratherthick and wind through the epidermis; there is alsosubstantial branching. These morphologic changescould explain the changed sensitivity of nerve end-ings in chronic pruritic skin disorders. The sensoryinnervation in epidermis not only changes in chronicpruritic skin diseases but also in an animal modelfor neuropathic pain.22 In addition, the epidermalexpression of MOR was significantly reduced inpatients with different chronic pruritic skin dis-eases.14,23 In particular, the hypertrophic epidermisof patients with chronic atopic dermatitis showsalmost no epidermal expression of MOR.14 Thisdown-regulation could also be observed on themRNA level.14 However, in this same study, nodown-regulation of MOR was observed in acutecontact dermatitis. The down-regulation of MOR onkeratinocytes in chronic pruritic skin diseases couldcause the following effects: (1) The endogenousligands for the MOR system are no longer bound tothe MOR on keratinocytes and therefore more lig-ands are available to bind to the MOR on epidermalnerve endings. This could result in an increase of the

itch signal to the CNS. (2) The epidermal nerve fibersare stretched in the hypertrophic epidermis, and thisincreases the sensitivity of the peripheral nerveendings, resulting again in an increased itch signal.The up-regulation of the epidermal MOR expressionin most of the chronic pruritic disorders after treat-ment with topical naltrexone could reduce pruritusby binding the free opioid ligands to the epidermalkeratinocytes. This makes fewer opioid ligandsavailable for binding to the epidermal nerve endings.In addition, naltrexone could have a direct effecton the opioid receptor signaling in peripheral nerveendings. All these effects lead to a decrease ofpruritus, as we have observed in the open andplacebo-controlled study described in this paper.Fig 5 summarizes the hypothesis of interactionsbetween the opioid receptor system on keratino-cytes and nerve endings and its relationship topruritus.

Overall, the naltrexone formulation shows clearadvantages over placebo as an antipruritic drug.However, in the double-blind, placebo-controlledstudy on patients with atopic dermatitis, the placeboalso showed some antipruritic effects. This again

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proves the well-known antipruritic potential ofa basic water-in-oil formulation. Dry skin plays acrucial part in the pathogenesis of most pruriticdisorders. A recent publication by Palmer et al24

stresses the important role of the epidermal barrierformation in atopic dermatitis. This epidermal barrieris severely disturbed by a loss-function-mutation inthe filaggrin gene in most of the patients with atopicdermatitis.24,25 The dry skin induces cracks, and thisexposes the epidermal nerve endings directly to theair. An ointment prevents the direct exposure of freenerve endings to air and irritants by occlusion. Thiscould result in an immediate reduction of pruritus.There are still many open questions about thepathophysiological role of opioid receptors in skinand the interaction between keratinocytes and freenerve endings in pruritus. However, these two stud-ies establish the clinical relevance of the MOR systemand the peripheral epidermal nerve endings inchronic pruritus. Further basic and clinical researchis warranted to open the way to new therapeuticapproaches for this burdensome symptom, pruritus.

We thank Dr Helen Langemann for proofreading themanuscript.

REFERENCES

1. Reinauer S, Goerz G. Juckreiz. Hautarzt 1996;47:229-42.

2. Friedman JD, Dello Buono FA. Opioid antagonists in the

treatment of opioid-induced constipation and pruritus. Ann

Pharmacother 2001;35:85-91.

3. Terra SG, Tsunoda SM. Opioid antagonists in the treatment

of pruritus from cholestatic liver disease. Ann Pharmacother

1998;32:1228-30.

4. Metze D, Reimann S, Beissert S, Luger T. Efficacy and safety

of naltrexone, an oral opiate receptor antagonist, in the

treatment of pruritus in internal and dermatological diseases.

J Am Acad Dermatol 1999;41:533-9.

5. Zylicz Z, Stork N, Krajnik M. Severe pruritus of cholestasis in

disseminated cancer: developing a rational treatment strategy.

A case report. J Pain Symptom Manage 2005;29:100-3.

6. Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C,

Turner ML, et al. Effects of naloxone infusions in patients with

the pruritus of cholestasis. A double-blind, randomized, con-

trolled trial. Ann Intern Med 1995;123:161-7.

7. Wolfhagen FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, Van

Buuren HR. Oral naltrexone treatment for cholestatic pruritus:

a double-blind, placebo-controlled study. Gastroenterology

1997;113:1264-9.

8. Terg R, Coronel E, Sorda J, Munoz AE, Findor J. Efficacy and

safety of oral naltrexone treatment for pruritus of cholestasis,

a crossover, double blind, placebo-controlled study. J Hepatol

2002;37:717-22.

9. Bergasa NV, Thomas DA, Vergalla J, Turner ML, Jones EA.

Plasma from patients with the pruritus of cholestasis induces

opioid receptor-mediated scratching in monkeys. Life Sci

1993;53:1253-7.

10. Jones EA, Dekker LR. Florid opioid withdrawal-like reaction

precipitated by naltrexone in a patient with chronic cholestasis.

Gastroenterology 2000;118:431-2.

11. Peer G, Kivity S, Agami O, Fireman E, Silverberg D, Blum M,

et al. Randomised crossover trial of naltrexone in uraemic

pruritus. Lancet 1996;348:1552-4.

12. Yuan CS, Foss IF, O’Connor M, Osinski J, Roizen MF, Moss J.

Efficacy of orally administered methylnaltrexone in decreasing

subjective effects after intravenous morphine. Drug Alcohol

Depend 1998;52:161-5.

13. Bigliardi PL, Bigliardi-Qi M, Buechner S, Rufli T. Expression of

mu-opiate receptor in human epidermis and keratinocytes.

J Invest Dermatol 1998;111:297-301.

14. Bigliardi-Qi M, Lipp B, Sumanovski LT, Buechner SA, Bigliardi

PL. Changes of epidermal mu-opiate receptor expression and

nerve endings in chronic atopic dermatitis. Dermatology

2005;210:91-9.

15. Johansson O, Wang L, Illiges M, Jiang Y. Intraepidermal nerves

in human skin: PGP 9.5 immunohistochemistry with special

reference to the nerve density in skin from different body

regions. J Peripher Nerv Syst 1999;4:43-52.

16. McArthur JC, Stocks EA, Hauer P, Cornblath DR, Griffin JW.

Epidermal nerve fiber density: normative reference range and

diagnostic efficiency. Arch Neurol 1998;55:1513-20.

17. Lauria G, Holland N, Hauer P, Cornblath DR, Griffin JW,

McArthur JC. Epidermal innervation: changes with aging,

topographic location, and in sensory neuropathy. J Neurol

Sci 1999;164:172-8.

18. Kauser S, Thody AJ, Schallreuter KU, Gummer CL, Tobin DJ.

beta-Endorphin as a regulator of human hair follicle melano-

cyte biology. J Invest Dermatol 2004;123:184-95.

19. Kauser S, Schallreuter KU, Thody AJ, Gummer C, Tobin DJ.

Regulation of human epidermal melanocyte biology by beta-

endorphin. J Invest Dermatol 2003;120:1073-80.

20. Stander S, Gunzer M, Metze D, Luger T, Steinhoff M. Locali-

zation of micro-opioid receptor 1a on sensory nerve fibers in

human skin. Regul Pept 2002;110:75-83.

21. Bigliardi-Qi M, Sumanovski LT, Buchner S, Rufli T, Bigliardi PL.

mu-Opiate receptor and beta-endorphin expression in nerve

endings and keratinocytes in human skin. Dermatology 2004;

209:183-9.

22. Grelik C, Allard S, Ribeiro-Da Silva A. Changes in nociceptive

sensory innervation in the epidermis of the rat lower lip skin

in a model of neuropathic pain. Neurosci Lett 2005;389:

140-5.

23. Bigliardi PL, Bigliardi-Qi M. Peripheral opiate receptor system

in human epidermis and itch, in peripheral opiate receptor

system in human epidermis and itch. In: Yosipovitch G, et al,

editors. New York: Marcel Dekker; 2004. pp. 97-106.

24. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H,

Lee SP, et al. Common loss-of-function variants of the epider-

mal barrier protein filaggrin are a major predisposing factor

for atopic dermatitis. Nat Genet 2006;38:441-6.

25. Irvine AD, McLean WH. Breaking the (un)sound barrier: filag-

grin is a major gene for atopic dermatitis. J Invest Dermatol

2006;126:1200-2.